Agonistas de receptores adrenérgicos α-2, Ácido Valproico y Carbamazepina como tratamiento adyuvante en la abstinencia alcohólica moderada-grave: Revisión Sistemática / α-2 adrenergic recipients, Valproic and Carbamazepine Acids as a adjuvant treatment in moderate-grave alcoholic abstinence: Systematic Review

La dependencia del alcohol se encuentra entre los principales factores de riesgo para la salud en la mayoría de los países desarrollados y en desarrollo.El éxito terapéutico en la abstinencia modera-grave podría incrementarse con tratamiento adyuvante a las benzodiacepinas. En nuestro medio los agonistas alfa2 (clonidina y dexmedetomidina), ácido valproico y carbamazepina son los de mayor uso. El objetivo de este trabajo fue realizar la búsqueda exhaustiva, análisis crítico y resumen de la evidencia para proporcionar una visión general de la efectividad de estos fármacos cuando son utilizado sin tiempo determinado de tratamiento comparados entre sí, contra ninguna intervención, placebo u otras intervenciones. Se realizó una búsqueda bibliográfica en bases de datos (Pubmed/MEDLINE, LILACs, EMBASE). Dos revisores seleccionaron, extrajeron los datos y evaluaron el riesgo de sesgo de los estudios incluidos de forma independiente mediante el software Covidence. Los desacuerdos fueron resueltos por consenso. Realizamos metanálisis utilizando RevMan 5. 3 y análisis de subgrupos por diseño de estudio. Se incluyeron 22 estudios donde ninguno de ellos presentó bajo riesgo de sesgo en todos los dominios, y la mayoría de los estudios presentaron al menos un dominio con alto riesgo de sesgo. Estudios con resultados estadísticamente bajos mostraron que la dexmedetomidina y el ácido valproico disminuyen los requerimientos de benzodiacepinas en pacientes que recibían placebo. Además, cuando se combinan ácido valproico con benzodiacepinas logran una disminución estable y continua de la abstinencia medido en escala CIWA-Ar. La clonidina fue la única descripta que presentaba disminución en la frecuencia cardiaca frente a placebo con alta significancia, situación clínica a tener presente frente al síndrome simpaticomimético que caracteriza al síndrome de abstinencia por alcohol.

Alcohol dependence is among the main risk factors for health in most developed and developing countries. Therapeutic success in moderate-Grave abstinence could be increased with adjuvant treatment to benzodiazepines. In our environment, agonists Alfa 2 (clonidine and dexmedetomidine), valproic acid and carbamazepine are the most used. The objective of this work was to carry out the thorough search, critical analysis and summary of the evidence to provide an overview of the effectiveness of these drugs when used without a certain time of treatment compared to each other, against any intervention, placebo or other interventions. A bibliographic search was carried out in databases (Pubmed/ Medline, Lilacs, Embase). Two reviewers selected, extracted the data and evaluated the bias risk of independently included studies using the COVIDENCE software. The disagreements were resolved by consensus. We perform meta-analysis using Revman 5. 3 and subgroup analysis by study design. 22 studies were included where none of them presented under a risk of bias in all domains, and most studies presented at least one domain with high bias risk. Studies with statistically low results showed that dexmedetomidine and valproic acid decrease the requirements of benzodiazepines in patients receiving placebo. In addition, when valproic acid is combined with benzodiazepines achieve a stable and continuous decrease in abstinence measured in CIWA-AR scale. Clonidine was the only one described that presented a decrease in heart rate against placebo with high significance, clinical situation to be in mind in front of the sympathomimetic syndrome that characterizes alcohol withdrawal syndrome

Fármacovigilancia de la carbamazepina en el Policlínico Marta Abreu. Santa Clara, 2022

Fundamento: en la práctica, el término estupefaciente se aplica a las especialidades farmacéuticas que contienen principios activos que actúan sobre el sistema nervioso central modificándolo y a las fórmulas magistrales con los mismos principios activos. Objetivo: caracterizar clínica y epidemiológicamente los pacientes que consumen carbamazepina en un área de salud del municipio de Santa Clara. Métodos: estudio descriptivo, transversal, en pacientes que consumen carbamazepina, pertenecientes al Policlínico Docente Marta Abreu, en el período del 1 de enero de 2021 al 1 de abril de 2022. Se incluyeron 209 pacientes y se midieron las siguientes variables: edad, sexo, número de pacientes según diagnósticos, número de pacientes según nuevos protocolos y tiempo de consumo del tratamiento. Resultados: predominó el grupo de edades de 51 a 60 con 43 pacientes (20,5 %), dentro de este grupo el sexo femenino (11,0 % del total); el diagnóstico predominante fue la epilepsia generalizada (93 pacientes). Predominó el sexo femenino, con 59 pacientes, y en ellas se encontró la mayor cantidad de expedientes vencidos, con un total de 16. Según nuevos protocolos, prevalecieron los pacientes con diagnóstico de neuralgia trigeminal, glosofaríngeo o facial (7 pacientes). En cuanto al tiempo de consumo predominaron los pacientes con igual diagnóstico a los anteriores y trastorno del comportamiento debido a enfermedad médica, ambos grupos con tratamientos de hasta tres años. Conclusiones: es importante el conocimiento sobre el uso y abuso de los estupefacientes así como mantener actualizado a todo el personal sanitario para lograr el óptimo control sobre estas sustancias.

Background: in practice, the term narcotic is applied to pharmaceutical specialties that contain active ingredients that act on the central nervous system, modifying it, and to master formulas with the same active ingredients. Objective: to characterize clinically and epidemiologically the patients who consume carbamazepine in a health area of the Santa Clara municipality. Methods: descriptive, cross-sectional study in patients consuming carbamazepine, belonging to the Marta Abreu Teaching Polyclinic, from January the 1st, 2021 to April the 1st, 2022. 209 patients were included and the following variables were measured: age, sex, number of patients according to diagnoses, number of patients according to new protocols and time of consumption of the treatment. Results: the age group from 51 to 60 predominated with 43 patients (20.5%), within this group the female sex (11.0% of the total); the predominant diagnosis was generalized epilepsy with a total of 93 patients. The female sex predominated with a total of 59 patients and in them the largest number of expired files was found, with a total of 16. According to new protocols, patients with a diagnosis of trigeminal, glossopharyngeal or facial neuralgia (7 patients) predominated. Regarding the time of consumption, patients with the same diagnosis as the previous ones and behavioral disorder due to a medical illness predominated, both groups with treatments of up to three years. Conclusions: knowledge about the use and abuse of narcotic drugs is important, as well as keeping all health personnel updated to achieve optimal control over these substances.

Paroxysmal Hemicrania-Trigeminal Neuralgia (PH-Tic) syndrome with no structural lesion in a Brazilian woman: the first case-report / Síndrome de Neuralgia Paroxística Hemicrânia-Trigêmea (PH-Tic) sem lesão estrutural em mulher brasileira: primeiro relato de caso

Introduction: In Brazil there is only one case report of a patient diagnosed with Paroxysmal Hemicrania-Trigeminal (PH-Tic) syndrome reported, however it was observed in a patient with Chiari I malformation. Objective: Here, we describe the first case of primary PH-Tic syndrome in the country. Method: Case report. CARE guideline was used to guide the structuring of this article. This case report was approved by the ethics committee and has been registered under the protocol number 70705623.7.0000.5440 on "Plataforma Brasil". Results:A 72-year-old woman with a five-month history of headaches was admitted at our headache outpatient clinic. The pain was sharp, intense, localized in the periorbital and left temporal regions. Blood counts, liver, renal and thyroid function were normal, as well as brain magnetic resonance imaging. Despite using carbamazepine, the patient had pain in only the left side of the face. Indomethacin was added until the dose of 100 mg a day and resulted in improvement of headache frequency. Conclusion: PH-Tic should be hypothesized in patients with short-lasting headaches associated with facial pain that partially improve with carbamazepine or indomethacin.

Introdução: No Brasil há apenas um relato de caso de paciente com diagnóstico de síndrome Paroxística Hemicrania-Trigeminal (PH-Tic), porém foi observado em um paciente com malformação de Chiari I. Objetivo: Descrevemos aqui o primeiro caso de síndrome PH-Tic primária no país. Método: Relato de caso. A diretriz CARE foi utilizada para orientar a estruturação deste artigo. Este relato de caso foi aprovado pelo comitê de ética e registrado sob o número de protocolo 70705623.7.0000.5440 na "Plataforma Brasil". Resultados: Uma mulher de 72 anos com história de cefaleias há cinco meses foi internada em nosso ambulatório de cefaleias. A dor era aguda, intensa, localizada nas regiões periorbital e temporal esquerda. Os hemogramas, as funções hepática, renal e tireoidiana estavam normais, assim como a ressonância magnética cerebral. Apesar do uso de carbamazepina, o paciente apresentava dor apenas no lado esquerdo da face. A indometacina foi adicionada até a dose de 100 mg ao dia e resultou em melhora da frequência da cefaleia. Conclusão: O PH-Tic deve ser hipotetizado em pacientes com cefaleias de curta duração associadas a dores faciais que melhoram parcialmente com carbamazepina ou indometacina.

Carbamazepine in the treatment of bipolar disorder: a systematic review / Carbamazepina no tratamento do transtorno bipolar: uma revisão sistemática

ABSTRACT Objective: Expand knowledge on the role and efficacy of carbamazepine (CBZ) in bipolar disorder (BD), based on original studies. Methods: The authors performed a systematic review of the scientific literature on the efficacy of CBZ in BD, using the PubMed/MEDLINE, Web of Science (ISI), and SciELO databases. The search terms were: ("carbamazepine") AND ("bipolar" OR "mania" OR "manic"). There was no restriction on the year of publication. Results: A total of 27 articles were selected. Among the selected articles, 14 evaluated the use of CBZ in the manic phase of BD, two in the depressive phase of BD, and 11 in the maintenance phase of BD. In the studies on the manic phase of BD, CBZ proved superior to placebo (PLA). As for the depressive phase of BD, there were two studies, both with small samples. In the maintenance phase, CBZ was inferior to lithium, and no studies compared CBZ to PLA. Conclusion: The results of the clinical studies suggest that CBZ is effective for the treatment of the manic phase. Regarding the treatment of acute depression and maintenance of BD, the results of the studies indicate that there is not enough data demonstrating the effectiveness of CBZ.

RESUMO Objetivo: Ampliar o conhecimento sobre o papel e a eficácia da carbamazepina (CBZ) no transtorno bipolar (TB), a partir de estudos originais. Métodos: Realizou-se uma revisão sistemática de literatura científica sobre a eficácia da CBZ no TB. Foram utilizadas as bases de dados PubMed/MEDLINE, Web of Science (ISI) e SciELO. Os termos de busca empregados foram: ("carbamazepine") AND ("bipolar" OR "mania" OR "manic"). Não houve restrição quanto ao período de publicação. Resultados: Foram selecionados 27 artigos. Entre os artigos selecionados, 14 avaliavam o uso da CBZ na fase de mania do TB, 2, na fase de depressão do TB e 11, na fase de manutenção do TB. A CBZ, nos estudos na fase de mania do TB, mostrou-se superior ao placebo (PLB). Em relação à fase de depressão no TB, havia dois estudos não controlados e com amostras pequenas. Quanto à fase de manutenção do TB, a CBZ foi inferior ao lítio, e não foram realizados estudos comparando com PLB. Conclusão: Os resultados dos estudos clínicos sugerem que a CBZ é eficaz para o tratamento da fase de mania. Em relação ao tratamento de depressão aguda e manutenção do TB, os resultados dos estudos indicam que não há dados suficientes que demonstrem a eficácia da CBZ.

Efectos adversos severos de los estabilizadores del ánimo: revisión de la literatura

Introducción: El trastorno bipolar TB es una enfermedad crónica y recurrente, según el DSM 5 se clasifica en los subtipos: trastorno bipolar I, trastorno bipolar II, ciclotimia y categorías residuales de formas atípicas que no encajan en los subtipos antes mencionados. La prevalencia del TB tipo I es similar entre hombres y mujeres, mientras que el TB tipo II ocurre con mayor frecuencia en mujeres. Según la Encuesta nacional de salud mental la prevalencia estimada del trastorno bipolar tipo I en Colombia es del 1,9% en los hombres y del 0,6% en las mujeres, para un porcentaje total de 1,3%. La etiología de TB incluye factores genéticos, neuro bioquímicos, neuro anatómicos, así como médicos y ambientales. El tratamiento del trastorno bipolar se puede dividir en dos fases distintas: manejo de un episodio inicial y tratamiento a largo plazo para prevenir recaídas, los fármacos utilizados comúnmente son: litio, antipsicóticos y anticonvulsivantes. Los estabilizadores del estado del ánimo aceptados por la FDA son: litio, carbamazepina, divalproato, y lamotrigina. Una reacción adversa a medicamentos (RAM) se define como cualquier respuesta nociva y no intencionada a un medicamento, constituye una importante causa de morbimortalidad y de aumento de los costes sanitarios. Los sistemas de farmaco-vigilancia permiten la identificación y prevención de los riesgos asociados al uso de medicamentos. Metodología: Se realizó una búsqueda bibliográfica mediante la base de datos PubMed, utilizando términos MeSH. Los criterios de inclusión utilizados fueron: a) Artículos publicados entre el año 2016 y 2021, b) Idioma inglés o español, c) Población a estudio: pacientes con diagnóstico de trastorno bipolar según criterios del DSM. Resultados: Se encontró que los efectos adversos severos de los estabilizadores del estado del ánimo como la carbamazepina y el ácido valproico son variados, se pueden presentar manifestaciones cutáneas como el síndrome de Stevens-Johnson, necrólisis epidérmica tóxica; manifestaciones hematológicas como anemia aplásica y manifestaciones hepáticas como lo son la hepatotoxicidad e hiperamonemia.

SUMMARY Introduction: Bipolar disorder TB is a chronic and recurrent disease, according to DSM 5 it is classified into subtypes: bipolar I disorder, bipolar II disorder, cyclothymia and residual categories of atypical forms that do not fit into aforementioned subtypes. Prevalence of type I TB is similar between men and women, while type II TB occurs more frequently in women. According to the National Mental Health Survey, estimated prevalence of type I bipolar disorder in Colombia is 1.9% in men and 0.6% in women, for a total percentage of 1.3%. Etiology of TB includes genetic, neuro biochemical, neuro anatomical, as well as medical and environmental factors. Treatment of bipolar disorder can be divided into two phases: management of an initial episode and long-term treatment to prevent relapses, drugs normally used are: Lithium, antipsychotics and anticonvulsants. Mood stabilizers accepted by FDA are: Lithium, carbamazepine, divalproex, and lamotrigine. An adverse drug reaction (ADR) is defined as any harmful and unintended response to a drug, it constitutes a major cause of morbidity and mortality and increased healthcare costs. Pharma-covigilance systems allow identification and prevention of risks associated with use of drugs. Methodology: A graphic search was performed using PubMed database, using MeSH terms. Inclusion criteria used were: a) Articles published between 2016 and 2021, b) English or Spanish language, c) Study population: Patients with a diagnosis of Bipolar Disorder according to DSM criteria. Results: It was found that severe adverse effects of mood stabilizers such as carbamazepine and valproic acid are varied, skin manifestations such as Stevens-Johnson's syndrome, toxic epidermal necrolysis can occur; Hematological manifestations such as aplastic anemia and hepatic manifestations such as hepatotoxicity and hyperammonemia.

Introdução: O transtorno bipolar TB é uma doença crônica e recorrente, segundo o DSM 5 é classificada em subtipos: transtorno bipolar I, transtorno bipolar II, ciclo-timia e categorias residuais de formas atípicas que não se enquadram nos subtipos mencionados. A prevalência de TB tipo I é semelhante entre homens e mulheres, enquanto a TB tipo II ocorre com mais frequência em mulheres. De acordo com a Pesquisa Nacional de Saúde Mental, a prevalência estimada de transtorno bipolar tipo I na Colômbia é de 1,9% nos homens e 0,6% nas mulheres, para um percentual total de 1,3%. A etiologia da TB inclui fatores genéticos, neuro-bioquímicos, neuro-anatômicos, médicos e ambientais. O tratamento do transtorno bipolar pode ser dividido em duas fases distintas: manejo de um episódio inicial e tratamento de longo prazo para prevenção de recidivas, os medicamentos comumente utilizados são: lítio, antipsicóticos e anticonvulsivantes. Os estabilizadores de humor aceitos pela FDA são: lítio, carbamazepina, divalproex e lamotrigina. Uma reação adversa a medicamento (ADR) é definida como qualquer resposta prejudicial e não intencional a um medicamento, é uma das principais causas de morbidade e mortalidade e aumento dos custos de saúde. Os sistemas de farmacovigilância permitem a identificação e prevenção dos riscos associados ao uso de medicamentos. Metodologia: Foi realizada pesquisa bibliográfica na base de dados PubMed, utilizando termos MeSH. Os critérios de inclusão utilizados foram: a) Artigos publicados entre 2016 e 2021, b) Língua inglesa ou espanhola, c) População do estudo: Pacientes com diagnóstico de Bipolar Desordem de acordo com os critérios do DSM. Resultados: Verificou-se que os efeitos adversos graves dos estabilizadores do humor como a carbamazepina e o ácido valpróico são variados, podendo ocorrer manifestações cutâneas como a síndrome de Stevens-Johnson, podendo ocorrer necrólise epidérmica tóxica; Manifestações hematológicas como anemia aplástica e manifestações hepáticas como hepatotoxicidade e hiperamonemia.

Assessment of carbamazepine acute toxicity in the cockle Cerastoderma edule through chemical, physiological and biochemical tools / Avaliação da toxicidade aguda da carbamazepina no berbigão Cerastoderma edule por meio de ferramentas químicas, fisiológicas e bioquímicas

The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 μg L-¹) of carbamazepine (CBZ). This anticonvulsant was found to alter the mussel behavior of by reducing its clearance rate (CR). Analysis of CBZ accumulation in tissues of C. edule was carried out using HPLC-UV after 48 or 96 hours of exposure. In addition, an overproduction of H2O2 by the bivalves was detected following exposure to CBZ but nitrite levels remained unchanged. Moreover, superoxide dismutase and catalase activities showed a significant increase in relation to their contact with CBZ. The activity of the biotransformation enzyme gluthatione-S-transferase did not change during exposure. Malondialdehyde (MDA) levels indicating cellular damage, increased when bivalves were exposed to 20 and 70 μg l-¹ of carbamazepine for 96 h CBZ. The results also indicate that acetylcholinesterase activity (AChE) was inhibited in all CBZ concentrations during the 48 h exposure period. However, during the 96 h exposure period, AChE was only inhibited at the highest concentration. Further studies are needed now for more exploration of the toxicity of CBZ since it could be bioaccumulable throughout the food web and may affect non-target organisms.

O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 μg L-¹) de carbamazepina (CBZ). Este anticonvulsivante alterou o comportamento do mexilhão, reduzindo sua taxa de depuração (CR). A análise do acúmulo de CBZ nos tecidos de C. edule foi realizada por HPLC-UV após 48 ou 96 horas de exposição. Além disso, uma superprodução de H2O2 pelos bivalves foi detectada após a exposição à CBZ, mas os níveis de nitrito permaneceram inalterados. Além disso, as atividades de superóxido dismutase e catalase apresentaram aumento significativo em relação ao contato com CBZ. A atividade da enzima de biotransformação glutationa-S-transferase não se alterou durante a exposição. Os níveis de malondialdeído (MDA), indicando dano celular, aumentaram quando os bivalves foram expostos a 20 e 70 μg l-1 de carbamazepina por 96 h CBZ. Os resultados também indicam que a atividade da acetilcolinesterase (AChE) foi inibida em todas as concentrações de CBZ durante o período de exposição de 48 horas. No entanto, durante o período de exposição de 96 horas, a AChE foi inibida apenas na concentração mais alta. Mais estudos são necessários agora para uma maior exploração da toxicidade da CBZ, uma vez que pode ser bioacumulável em toda a cadeia alimentar e pode afetar organismos não alvo.

Assessment of carbamazepine acute toxicity in the cockle Cerastoderma edule through chemical, physiological and biochemical tools

Abstract The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 g L-1) of carbamazepine (CBZ). This anticonvulsant was found to alter the mussel behavior of by reducing its clearance rate (CR). Analysis of CBZ accumulation in tissues of C. edule was carried out using HPLC-UV after 48 or 96 hours of exposure. In addition, an overproduction of H2O2 by the bivalves was detected following exposure to CBZ but nitrite levels remained unchanged. Moreover, superoxide dismutase and catalase activities showed a significant increase in relation to their contact with CBZ. The activity of the biotransformation enzyme gluthatione-S-transferase did not change during exposure. Malondialdehyde (MDA) levels indicating cellular damage, increased when bivalves were exposed to 20 and 70 g l-1 of carbamazepine for 96 h CBZ. The results also indicate that acetylcholinesterase activity (AChE) was inhibited in all CBZ concentrations during the 48 h exposure period. However, during the 96 h exposure period, AChE was only inhibited at the highest concentration. Further studies are needed now for more exploration of the toxicity of CBZ since it could be bioaccumulable throughout the food web and may affect non-target organisms.

Resumo O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 g L-1) de carbamazepina (CBZ). Este anticonvulsivante alterou o comportamento do mexilhão, reduzindo sua taxa de depuração (CR). A análise do acúmulo de CBZ nos tecidos de C. edule foi realizada por HPLC-UV após 48 ou 96 horas de exposição. Além disso, uma superprodução de H2O2 pelos bivalves foi detectada após a exposição à CBZ, mas os níveis de nitrito permaneceram inalterados. Além disso, as atividades de superóxido dismutase e catalase apresentaram aumento significativo em relação ao contato com CBZ. A atividade da enzima de biotransformação glutationa-S-transferase não se alterou durante a exposição. Os níveis de malondialdeído (MDA), indicando dano celular, aumentaram quando os bivalves foram expostos a 20 e 70 g l-1 de carbamazepina por 96 h CBZ. Os resultados também indicam que a atividade da acetilcolinesterase (AChE) foi inibida em todas as concentrações de CBZ durante o período de exposição de 48 horas. No entanto, durante o período de exposição de 96 horas, a AChE foi inibida apenas na concentração mais alta. Mais estudos são necessários agora para uma maior exploração da toxicidade da CBZ, uma vez que pode ser bioacumulável em toda a cadeia alimentar e pode afetar organismos não alvo.

Assessment of carbamazepine acute toxicity in the cockle Cerastoderma edule through chemical, physiological and biochemical tools / Avaliação da toxicidade aguda da carbamazepina no berbigão Cerastoderma edule por meio de ferramentas químicas, fisiológicas e bioquímicas

The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 µg L-1) of carbamazepine (CBZ). This anticonvulsant was found to alter the mussel behavior of by reducing its clearance rate (CR). Analysis of CBZ accumulation in tissues of C. edule was carried out using HPLC-UV after 48 or 96 hours of exposure. In addition, an overproduction of H2O2 by the bivalves was detected following exposure to CBZ but nitrite levels remained unchanged. Moreover, superoxide dismutase and catalase activities showed a significant increase in relation to their contact with CBZ. The activity of the biotransformation enzyme gluthatione-S-transferase did not change during exposure. Malondialdehyde (MDA) levels indicating cellular damage, increased when bivalves were exposed to 20 and 70 µg l-1 of carbamazepine for 96 h CBZ. The results also indicate that acetylcholinesterase activity (AChE) was inhibited in all CBZ concentrations during the 48 h exposure period. However, during the 96 h exposure period, AChE was only inhibited at the highest concentration. Further studies are needed now for more exploration of the toxicity of CBZ since it could be bioaccumulable throughout the food web and may affect non-target organisms.

O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 µg L-1) de carbamazepina (CBZ). Este anticonvulsivante alterou o comportamento do mexilhão, reduzindo sua taxa de depuração (CR). A análise do acúmulo de CBZ nos tecidos de C. edule foi realizada por HPLC-UV após 48 ou 96 horas de exposição. Além disso, uma superprodução de H2O2 pelos bivalves foi detectada após a exposição à CBZ, mas os níveis de nitrito permaneceram inalterados. Além disso, as atividades de superóxido dismutase e catalase apresentaram aumento significativo em relação ao contato com CBZ. A atividade da enzima de biotransformação glutationa-S-transferase não se alterou durante a exposição. Os níveis de malondialdeído (MDA), indicando dano celular, aumentaram quando os bivalves foram expostos a 20 e 70 µg l-1 de carbamazepina por 96 h CBZ. Os resultados também indicam que a atividade da acetilcolinesterase (AChE) foi inibida em todas as concentrações de CBZ durante o período de exposição de 48 horas. No entanto, durante o período de exposição de 96 horas, a AChE foi inibida apenas na concentração mais alta. Mais estudos são necessários agora para uma maior exploração da toxicidade da CBZ, uma vez que pode ser bioacumulável em toda a cadeia alimentar e pode afetar organismos não alvo.

Síndrome de reacción a fármacos con eosinofilia y síntomas sistémicos inducido por carbamazepina de liberación prolongada: reporte de un caso

El síndrome de reacción a fármacos con eosinofilia y síntomas sistémicos es una reacción de hipersensibilidad a fármacos poco común, pero con una alta mortalidad, por ello se requiere un diagnóstico precoz y un manejo oportuno. Presentamos el caso de una mujer de 32 años con diagnóstico de epilepsia y trastorno esquizofreniforme orgánico, secundarios a encefalitis viral, y que ha recibido tratamiento con múltiples fármacos. Tres semanas después de añadir carbamazepina de liberación prolongada a su terapia habitual, la paciente presentó una erupción cutánea difusa tipo habón, edema facial, fiebre, linfadenopatía, leucocitosis con eosinofilia y elevación de las transaminasas. La administración de la carbamazepina fue suspendida, se administró antihistamínicos y glucocorticoides por vía oral, y la paciente mejoró.

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but highly lethal drug hypersensitivity reaction. Thus, it requires an early diagnosis and timely management. We present the case of a 32-year-old female patient with a diagnosis of epilepsy and organic schizophreniform disorder, secondary to viral encephalitis, who was treated with multiple drugs. Three weeks after the addition of extended-release carbamazepine to her usual therapy, the patient presented a diffuse welt-type skin rash, facial edema, fever, lymphadenopathy, leukocytosis with eosinophilia and elevated transaminases. Carbamazepine administration was discontinued, antihistamines and glucocorticoids were administered orally, and the patient showed a remarkable improvement.

Reporte de caso: purpura diseminada como primera manifestación de síndrome de dress / Case report: purpuriform lesions as the first manifestation of dress syndrome

RESUMEN El síndrome de DRESS es una reacción adversa severa a fármacos presentándose más comúnmente con anticonvulsivantes y antibióticos. Se estima que su mortalidad alcanza el 10%; clínicamente se presenta con fiebre, linfadenopatías, erupciones cutáneas morbiliformes y compromiso deórganos terminal. Las reacciones adversas cutáneas medicamentosas se presentan en más de la mitad de los pacientes que están recibiendo medicamentos sistémicos tales como la carbamazepina.

SUMMARY DRESS syndrome is a severe adverse reaction to medicament which is most commonly presentedwith anticonvulsants and antibiotics. It is estimated that the mortality reaches10%;clinically the patients presentit with fever, lymphadenopathies, morbilliform cutaneous eruptions and terminal organ involvement. Adverse skin reactions to medications occur in more than half of patients who have received systemic medications, such as anticonvulsants.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers / Dos pacientes que tomaban inductores necesitaron dosis altas de medicamentos metabolizados en gran medida por el CYP3A4 para alcanzar concentraciones terapéuticas

ABSTRACT Introduction: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. Methods: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. Results: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000 mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. Conclusions: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

RESUMEN Introducción: Durante sus últimos 20 años de práctica, el último autor ha identificado estos 2 infrecuentes casos que necesitaban dosis extremadamente altas de medicaciones metabolizadas por el CYP3A4 para alcanzar y mantener concentraciones séricas terapéuticas. Métodos: La gran capacidad metabólica de estos 2 pacientes se demostró por los bajos cocientes entre concentración y dosis (C/D) de varias medicaciones metabolizadas por el CYP3A4. Resultados: El caso 1 se caracterizaba por una historia de altas dosis de carbamazepina (1.500 mg/día) y la necesidad de tomar 170 mg de diazepam en 2 días para facilitar una limpieza dental. La gran actividad de la isoenzima CYP3A4 se manifestó por una gran capacidad metabólica de quetiapina y diazepam, cuya normalización tardó más de 1 año tras la toma de un inductor, fenitoína. El caso 2 tambien era muy sensible a la inducción, lo cual se demuestra por los bajos cocientes C/D de carbamazepina, risperidona y paliperidona. Las dosis de carbamazepina (2.800 mg/día) y risperidona (20 mg/día) de este segundo paciente son las más altas nunca vistas por el último autor. La inducción de risperidona duró muchos meses y su metabolismo era normal 3 años después de interrumpir la carbamazepina. El cociente C/D de olanzapina era normal para la inducción. Conclusiones: Nunca se habían descrito casos similares de dosis tan altas de medicaciones metabolizadas por el CYP3A4. Se especula con que estos pacientes podrían tener unos perfiles genéticos inusuales en los receptores nucleares que regulan la inducción de medicamentos.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers.

INTRODUCTION: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. METHODS: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. RESULTS: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. CONCLUSIONS: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

Intoxicación por carbamazepina: reporte de un caso tratado con hemodiálisis de alto flujo / Carbamazepine poisoning: case report treated with high-flux hemodialysis / Intoxicação por carbamazepina: relato de um caso tratado com hemodiálise de alto fluxo

Resumen: La carbamazepina es un medicamento que en sobredosis puede causar alteraciones neurológicas y cardiovasculares que ponen en peligro la vida, ya sea por efecto directo o por su metabolito activo 10,11-epóxido. En los pacientes intoxicados con carbamazepina que presentan una mala respuesta al tratamiento inicial o una intoxicación severa, puede requerirse el empleo de técnicas extracorpóreas de eliminación como la hemodiálisis o la hemoperfusión. Describimos el caso de una mujer de 71 años que ingirió una sobredosis de carbamazepina, diazepam y zolpidem en un intento suicida, la cual no respondió favorablemente al tratamiento conservador, por lo que fue necesario llevar a cabo dos sesiones de hemodiálisis de alto flujo. Al término de las sesiones, se normalizó la concentración sérica de carbamazepina y la paciente mostró mejoría de su condición clínica. Con el desarrollo de membranas de hemodiálisis de alto flujo, ha sido posible incrementar el aclaramiento de xenobióticos que eran considerados como moderadamente dializables, lo cual podría ampliar las expectativas respecto a la utilidad de la hemodiálisis en el tratamiento de los pacientes intoxicados por éste y otros xenobióticos.

Abstract: Carbamazepine is a drug that in overdose can cause life-threatening neurological and cardiovascular abnormalities, either by direct effect or by its active metabolite 10,11-epoxide. In carbamazepine poisoned patients with poor response to initial treatment or severe poisoning, may require the use of extracorporeal elimination techniques such as hemodialysis or hemoperfusion.We describe the case of a 71-year-old woman who ingested an overdose of carbamazepine, diazepam and zolpidem in a suicide attempt, who did not respond favorably to the conservative treatment, so it was necessary to conduct two sessions of high-flux hemodialysis. At the end of the sessions the serum concentration of carbamazepine was normalized and patient showed improvement in her clinical condition. With the development of high-flux hemodialysis membranes it has been possible to increase the clearance of xenobiotics that were considered as moderately dialyzable, which could extend the expectations regarding the usefulness of hemodialysis in the treatment of poisoned patients by this and other xenobiotics.

Resumo: A carbamazepina é um medicamento que em caso de sobredosagem pode causar alterações neurológicas e cardiovasculares potencialmente fatais, seja por efeito direto ou por seu metabólito ativo 10,11-epóxido. Em pacientes intoxicados com carbamazepina que apresentam uma pobre resposta ao tratamento inicial ou envenenamento grave o uso de técnicas de eliminação extracorpórea como hemodiálise ou hemoperfusão pode ser necessário. Descrevemos o caso de uma mulher de 71 anos que ingeriu uma dose excessiva de carbamazepina, diazepam e zolpidem em uma tentativa de suicídio, que não respondeu favoravelmente ao tratamento conservador, por isso foi necessário realizar duas sessões de hemodiálise de alto fluxo. Ao final das sessões a concentração sérica de carbamazepina foi normalizada e a paciente apresentou melhora em sua condição clínica. Com o desenvolvimento de membranas de hemodiálise de alto fluxo foi possível aumentar a depuração de xenobióticos considerados moderadamente dialisáveis, o que poderia ampliar as expectativas em relação à utilidade da hemodiálise no tratamento de pacientes intoxicados por este e outros xenobióticos.

Síndrome de sensibilidad a drogas con eosinofilia y síntomas sistémicos (DRESS) atípico por carbamazepina, a propósito de un caso pediátrico / Drug sensitivity syndrome with eosinophilia and atypical symptoms (DRESS) by carbamazepine: a case report

Introducción: El síndrome de sensibilidad a drogas con eosinofilia y síntomas sistémicos (DRESS) generalmente es acompañado por eosinofilia. Es una enfermedad que pone en peligro la vida del paciente. Se presenta como reacción adversa a infecciones y a medicamentos, usualmente asociada al uso de antiepilépticos. Caso clínico: Paciente de 6 años, masculino, con antecedente de Epilepsia de reciente diagnóstico, que consultó en Servicio de Urgencias dos semanas después de iniciar tratamiento con Carbamazepina, por cuadro caracterizado por eritema de predominio facial, exacerbado con la exposición al sol. Posteriormente presentó fiebre con episodios hasta 40 °C, que se asoció a convulsiones. Después de un exhaustivo estudio se concluyó DRESS atípico (sin eosinofilia), iniciando tratamiento corticoideo con favorable respuesta clínica. Discusión: El síndrome de DRESS, es una enfermedad de difícil diagnóstico por sus múltiples diagnósticos diferenciales y falta de criterios diagnósticos. Es esencial la suspensión inmediata del fármaco causante, para evitar progresión de la enfermedad e iniciar tratamiento precoz.

Background: The drug sensitivity syndrome with eosinophilia and systemic symptoms (DRESS) is usually accompanied by eosinophilia. It is a disease that endangers the life of the patient. It occurs as an adverse reaction to infections and medications, usually associated with the use of antiepileptics. Case report: A 6-year-old patient, male, with a recent diagnosis of epilepsy, who consulted the Emergency Department two weeks after initiating treatment with Carbamazepine because of a condition characterized by facial predominance erythema, exacerbated by sun exposition. Subsequently presented fever with episodes up to 40 ° C, which was associated with seizures. After an exhaustive study, atypical DRESS syndrome (without eosinophilia) was made, initiating corticoid treatment with favorable clinical response. Discussion: DRESS syndrome is a disease difficult to diagnose because of its multiple differential diagnoses and lack of diagnostic criteria. Immediate suspension of the causative drug is essential to prevent progression of the disease and initiate early treatment Keywords: Drug Hypersensitivity Syndrome, Carbamazepine, Corticoid.

Síndrome de sensibilidad a fármacos con eosinofilia y síntomas sistémicos debido a la carbamazepina: Caso pediátrico / Drug reaction with eosinophilia and systemic symptoms due to carbamazepine: Pediatric case

Entre las reacciones medicamentosas graves en la piel, se encuentran el síndrome de Stevens-Johnson, la necrólisis epidérmica tóxica y el síndrome de sensibilidad a fármacos con eosinofilia y síntomas sistémicos (drug reaction with eosinophilia and systemic symptoms; DRESS, por sus siglas en inglés), que son poco comunes en la población pediátrica (incidencia: 1/1000-10 000 niños), sin embargo, tienen mal pronóstico. El síndrome de sensibilidad a fármacos con eosinofilia y síntomas sistémicos consiste en erupciones cutáneas, alteraciones hematológicas, linfadenopatía y afectación de órganos. Se presenta el caso de un paciente masculino de 12 años que desarrolló esta patología después de iniciar el tratamiento anticonvulsivo con carbamazepina. Se considera que es importante que el personal de la salud tenga conocimiento de esta enfermedad para que sea incluida entre los diagnósticos diferenciales de pacientes con afecciones similares, ya que este síndrome es potencialmente mortal.

Severe skin reactions include Stevens-Johnson Syndrome, toxic epidermal necrolysis and Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, which are uncommon in the pediatric population (incidence 1/1000-10 000 children), but they have bad prognosis. Drug-sensitive Syndrome with eosinophilia and systemic symptoms consists in rash, hematological abnormalities, lymphadenopathy and organ involvement. We report the case of a 12-year-old male patient who developed this pathology after initiating anticonvulsant therapy with carbamazepine. We consider that it is important to be aware of this disease and to include it among the differential diagnoses in patients with similar conditions because this syndrome is life-threatening.

Role of voltage-gated sodium channel blockers in the treatment of chronic pain: Potential uses in clinical practice based on available evidence. / Papel de los bloqueadores de los canales de sodio dependientes de voltaje en el tratamiento del dolor crónico: usos potenciales en la práctica clínica según la evidencia disponible.

Once patients have failed first line therapy, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose amongst alternative agents, an understanding of pharmacology, pharmacokinetics, and available evidence in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine acetate) for adjunct pain medication management; including research updates in pharmacology, pharmacokinetics, and evidence for pain along on this therapeutic group with promising future areas of research. Although evidence for voltage-gated sodium channel blockers in chronic pain management is limited, emerging research has identified this area as promising for additional clinical trials to better guide clinical practice.

EPICON consensus: recommendations for proper management of switching to eslicarbazepine acetate in epilepsy. / Consenso Delphi EPICON: recomendaciones sobre el manejo adecuado del cambio a acetato de eslicarbazepina en epilepsia.

INTRODUCTION: The objective of the EPICON Project is to develop a set of recommendations on how to adequately switch from carbamazepine (CBZ) and oxcarbazepine (OXC) to eslicarbazepine acetate (ESL) in some patients with epilepsy. METHODS: A steering committee drafted a questionnaire of 56 questions regarding the transition from CBZ or OXC to ESL in clinical practice (methodology and change situation). The questionnaire was then distributed to 54 epilepsy experts in 2 rounds using the Delphi method. An agreement/disagreement consensus was defined when a median ≥ 7 points or ≤ 3 was achieved, respectively, and a relative interquartile range ≤ 0.40. We analysed the results obtained to reach our conclusions. RESULTS: Our main recommendations were the following: switching from CBZ to ESL must be carried out over a period of 1 to 3 weeks with a CBZ:ESL dose ratio of 1:1.3 and is recommended for patients who frequently forget to take their medication, those who work rotating shifts, polymedicated patients, subjects with cognitive problems, severe osteoporosis-osteopaenia, dyslipidaemia, or liver disease other than acute liver failure, as well as for men with erectile dysfunction caused by CBZ. The transition from OXC to ESL can take place overnight with an OXC:ESL dose ratio of 1:1 and it is recommended for patients who frequently forget to take their medication, those who work rotating shifts, polymedicated patients, or those with cognitive problems. The transition was not recommended for patients with prior rash due to CBZ or OXC use. CONCLUSION: The EPICON Project offers a set of recommendations about the clinical management of switching from CBZ or OXC to ESL, using the Delphi method.

Lesión hepática severa inducida por carbamazepina asociado a necrolisis epidérmica tóxica / Severe hepatic injury induced by carbamazepine associated with toxic epidermal necrolysis

La necrolisis epidérmica toxica y el síndrome de Stevens- johnson son trastornos raros y mortales, caracterizado por una lesión severa de la piel y mucosa. Estos trastornos son una misma condición, se diferencia por el grado de afección de la superficie corporal total. La reacción de hipersensibilidad de los fármacos es la etiología más frecuente de estas dos entidades; por otro lado, el hígado es también una diana de las lesiones causadas por medicamentos, pudiendo conducir hasta una hepatitis severa y hasta en peor de los casos falla hepática aguda, llevando a ictericia, encefalopatía y coagulopatia. El presente caso es un paciente que sufre un trauma craneoencefálico con presencia de hematoma subdural, días después inicia el consumo de carbamazepina como profilaxis anticonvulsivante y acetaminofén para el dolor, generando lesión en piel que comprometían más de un 30% de la superficie corporal, lesión hepática severa con elevación marcada de transaminasas y encefalopatía, que bien podría corresponder al hematoma subdural o a la lesión hepática; esto genero gran interés.

Toxic epidermal necrolysis and Stevens Johnson syndrome are rare and fatal disorders, characterized by severe skin and mucosal injury. These disorders are the same condition, it is differentiated by the degree of affection of the total body surface. The hypersensitivity reaction of drugs is the most frequent etiology of these two entities; On the other hand, the liver is also a target of lesions caused by medications, which can lead to severe hepatitis and even worse acute liver failure, leading to jaundice, encephalopathy and coagulopathy. The present case is a patient suffering a head trauma with the presence of subdural hematoma, days after the start of consumption of carbamazepine as anticonvulsant prophylaxis and acetaminophen for pain, generating skin lesion that compromised more than 30% of the body surface, injury severe hepatic disease with marked elevation of transaminases and encephalopathy, which could well correspond to subdural hematoma or hepatic damage; This generated great interest.

DRESS: relato de caso com estudo genético / DRESS syndrome: case report with genetic testin

A síndrome de hipersensibilidade a drogas com eosinofilia e sintomas sistêmicos (DRESS) é uma rara reação adversa a drogas com potencial de morte e sequelas em longo prazo. Os anticonvulsivantes aromáticos estão entre os medicamentos mais relacionados. Relatamos um caso de DRESS em associação com o alelo HLA-A*31:01, destacando aspectos clínico-laboratoriais, abordagem diagnóstica e acompanhamento ambulatorial de sequelas tardias. Homem com 69 anos, natural do Japão, internado com suspeita clínica de DRESS. Havia iniciado carbamazepina 4 semanas antes do rash cutâneo para tratamento de epilepsia. Apresentou biópsia cutânea compatível com farmacodermia. O paciente foi tratado com prednisolona por 4 meses. A tipagem HLA-A-B-DRB1 por PCR-RSSO (ONE LAMBDA) e SSP alelo específico revelou HLA relacionado a reações de hipersensibilidade à carbamazepina. O teste de contato realizado com carbamazepina a 10% no primeiro ano após a reação foi positivo. A restrição futura da classe de anticonvulsivantes aromáticos foi recomendada. Oito meses após a aparente resolução clínica da DRESS, o paciente desenvolveu aumento dos anticorpos antitireoideanos e doença de Hashimoto. Treze meses após a o início da reação, foi observado aumento nos títulos de FAN, sem manifestações clínicas. Este relato de caso descreve aspectos clínico-laboratoriais típicos de DRESS relativos ao diagnóstico clínico-laboratorial e histopatológico, bem como evolução clínica em curto e longo prazos. A abordagem farmacogenética e o teste de contato foram importantes para a confirmação da imputabilidade da carbamazepina na etiologia da DRESS.

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is a rare, potentially fatal adverse reaction to drugs that may have long-term sequelae. Aromatic anticonvulsants are among the drugs most commonly associated with DRESS. We report a case of DRESS associated with allele HLA-A*31:01, with emphasis on clinical and laboratory findings, the diagnostic approach adopted, and outpatient follow-up of late sequelae. A 69-year old Japanese male patient was admitted with a clinical suspicion of DRESS. He had started carbamazepine treatment for epilepsy 4 weeks before the rash. He presented skin biopsy compatible with pharmacodermia. The patient was treated with prednisolone for 4 months. HLA-A-B-DRB1 typing using the PCRRSSO technique (ONE LAMBDA) and specific SSP allele revealed HLA related to hypersensitivity reactions to carbamazepine. The skin test performed with carbamazepine 10% on the first day after the reaction resulted positive. Future restriction of aromatic anticonvulsants was recommended. Eight months after the apparent clinical resolution of DRESS, the patient showed increased levels of antithyroid antibodies and Hashimoto disease. Thirteen months after the onset of the reaction, increased FAN results were observed, with no clinical manifestations. This case report describes clinical and laboratory aspects of DRESS related to clinical, laboratory, and histopathological diagnosis, as well as clinical evolution in the short and long terms. The pharmacogenetic approach and the skin test were important to confirm the imputability of carbamazepine in the etiology of DRESS.

Paroxismia vestibular: reporte de un caso / Vestibular paroxysmia: case report

Presentamos el caso de un paciente joven quien presenta 4 a 5 crisis diarias de vértigo espontáneo de segundos de duración, todos o casi todos los días desde hace 9 meses. Estas crisis no tienen gatillo posicional, y hay completa ausencia de sintomatologia entre crisis. Como discutimos en el artículo, este cuadro coíncide con los recientemente publicados criterios para una paroxismia vestibular, entidad supuestamente secundaria a la compresión neurovascular del nervio vestibular. El paciente respondió de forma inmediata y completa a carbamazepina a dosis bajas, el tratamiento de elección en la paroxismia vestibular.

We present the case of a young patient, with a 9-month long history of 4 to 5 daily spells of spontaneous vertigo, each lasting only seconds. There is no positional trigger, and there is a complete lack of symptoms between attacks. As is discussed in the article, this matches the recently published criteria for Vestibular Paroxysmia, an entity allegedly secondary to neurovascular compression of the vestibular nerve. The patient responded immediately and completely to carbamazepine at low dosage, the preferred treatment for vestibular paroxysmia.